Mandelamidocephalosporins with improved properties

ABSTRACT

7-Mandelamido-3-(1-oxidopyridylthiomethyl)-3-cephem-4-carboxylic acid and substituted derivatives which have antibacterial activity are disclosed.

waited tates Frazee et al.

1 MANDELAMIDOCEPHALOSPORINS WITH IMPROVED PROPERTIES [75] Inventors:James S. Frazee, Collingswood,

N.J.; Timothy Yu-Wen Jen, Broomall, Pa.

[73] Assignee: SmithKline Corporation,

Philadelphia, Pa.

[22] Filed: July 5, 1973 [21] Appl. No.: 376,653

[52] (1.8. CI. 260/243 C; 424/246 [51] Int. Ci C07d 99/24 [58] Field ofSearch 260/243 C [451 May 20, 1975 Primary ExaminerNicholas S. RizzoAttorney, Agent, or Firm-Stuart R. Suter; Alan D. Lourie; William H.Edgerton [57] ABSTRACT 7-Mande1amido-3-( 1-oxidopyridylthiomethyl)-3-cephem-4-carboxylic acid and substituted derivatives which haveantibacterial activity are disclosed.

5 Claims, No Drawings MANDELAMIDOCEPHALOSPORINS WITH IMPROVED PROPERTIESThis invention relates to cephalosporin compounds havingl-oxidopyridylthiomethyl and mandelamido groups at positions 3 and 7,respectively. The compounds are broad spectrum antibacterials.

Various unsubstituted or substituted mandelamido cephalosporins havebeen reported. 7-Mandelamidocephalosporanic acid is disclosed in US.Pat. No. 3,167,549 along with mono or disubstituted derivatives. 1n U.S.Pat. No. 3,641,021 unsubstituted or monosubstitutedmandelamidocephalosporins with a thiadiazoylthiomethyl or atetrazolylthiomethyl group at position 3 are reported. Cephalosporinswith a pyridylthiomethyl-N-oxide group at position 3 are described inBelgian Pat. Nos. 762725, 770804, and 777260 and Japanese Pat. No.4717793. For example, 7-( a-aminophenylacetamido)-3-( l-oxido-2-pyridylthiomethyl)-3-cephem-4-carboxylic acid and other 7-acylamidoderivatives are reported in Belgian Pat. No. 770804.

The compounds of this invention are represented by the formula coon lwhere R is hydrogen, alkyl of C -C alkoxy of C C fluoro, chloro, bromo,hydroxy, amino, nitro, or trifluoromethyl.

Preferred compounds are those where R is phydroxy, m-amino,m-trifluoromethyl, m-nitro, mchloro, pmethyl, or hydrogen. Alsopreferred are the compounds where the pyridyl moiety is bonded at the 2position on the pyridine ring. Particularly preferred are thecompoundswhere R is hydrogen.

Pharmaceutically acceptable salts of the compounds are also within thescope of the invention. Bases which form pharmaceutically acceptablesalts with acids are well known to those skilled in the art. Forexample, common cations include sodium, potassium, and ammonium.

The compounds are prepared by the reaction of amandelamidocephalosporanic acid with a mercaptopyridine-N-oxide or asalt thereof. The 3-acetoxy group is displaced by the mercapto compoundto give the compounds of the invention. Alternatively the compounds areprepared by displacement of the 3-acetoxy of 7-aminocephalosporanic acid(7-ACA) with the above mercapto compound and then acylation with thedesired mandelic acid. During the acylation reaction;

the hydroxy group of the mandelic acid must be protected with aprotecting group, many of which are known in the art. For example, thetetrahydropyranyl ether or the formate, dichloroacetate, or other estermay be used. Standard methods are used to remove the protecting groupsafter the acylation reaction is completed.

The carboxylic acid is activated prior to the acylation reaction bystandard methods, such as the acid chloride, mixed anhydride oractivated ester. All the above procedures are well-known reactions, thechoice of exact methods and conditions being within the ability of oneskilled in the art and not critical to our invention.

Due to the asymmetric carbon in the mandelic acid side chain opticalisomers exist. The diasteromers having the D configuration arepreferred; however, those having the L configuration and the racemicmixtures are within the scope of the invention.

The compounds have broad spectrum antibacterial activity. In vitro testsindicate the compounds to have activity against both Gram-positive andGram-negative organisms. Studies in mice showed protection against E.coli and Klebsiella pneumoniae infections. For example,7-mandelamido-3-(l-oxido-2-pyridylthiomethyl)- 3-cephem-4-carboxylicacid gave an ED of 9.4 and 3 mg/kg against E. coli and K. pnezmzoniae.respectively. when administered subcutaneously to infected mice.

The compounds are formulated as other cephalosporins by standard methodswhich are well known in the art. Daily dosages range from 1-8 gramsdepending on the subject and infection being treated. These total dailydosages are usually divided and administered at regular intervals.

The following examples are given to illustrate the invention and are notto be considered limitative.

EXAMPLE 1 7-(D-Mandelamido)-3-( l-oxido-2-pyridylthiomethyl3-cephem-4-carboxylic acid.

A solution of 7-(D-mandelamido)cephalosporanic acid, methanolate (2.41g, 5 mmol) and Nal-lCO (420 mg, 5 mmol) in H 0 (30 ml) was treated witha solution of sodium-2-mercaptopyridine-N-oxide (900 mg, 6 mmol) in H 0(5 ml). After 24 hours at 58, the reaction was cooled, diluted withacetone (30 ml), and acidified with 3N HCl to pH 1. The acidic solutionwas concentrated until crystallization began, and then chilled. Thecrystalline product was filtered, washed with acetone and ether anddried; 1.6 g (68 percent), mp 216 (dec.).

EXAMPLE 2 When 7-(4-methylmandelamido)cephalosporanic acid,7-(4-hydroxymandelamido)cephalosporanic acid,7-(4-methoxymandelamido)cephalosporanic acid, 7-(3-nitromandelamido)cephalosporanic acid, 7-(3- chloromandelamido)cephalosporanic acid, 7-(3- aminomandelamido)cephalosporanic acid or7-(3- trifluoromethylmandelamido)cephalosporanic acid is substituted formandelamidocephalosporanic acid in Example 1 the following compounds areobtained.

7-(4-methylmandelamido)-3-( l-oxido-2-pyridylthiomethyl)-3-cephem-4-carboxylic acid7-(4-hydroxymandelamido)-3-( l-oxido-Z-pyridylthiomethyl)-3-cephem-4-carboxylic acid7-(4-methoxymandelamido)-3-( l-oxido-Z-pyridylthiomethyl)-3-cephem-4-carboxy1ic acid 7-(3-nitromandelamido)-3-( l-oxido-2-pyridylthiomethyl)-3-cephem-4-carboxylic acid7-(3-chloromandelamido)-3-( l-oxido-2-pyridylthiomethyl)-3-cephem-4-carboxylic acid 7-(3-aminomandelamido)-3-(1-oxido-2- pyridylthiomethyl)-3-cephem-4-carboxylic acid 7-(3-trifluoromethylmandelamido )-3-( l-oxido-2-pyridylthiomethyl)-3-cephem-4-carboxylic acid EXAMPLE 3 Whensodium-4-mercaptopyridine-N-oxide is substituted forsodium-2-mercaptopyridine-N-oxide in Examples l and 2 the corresponding3-(l-oxido-4- pyridylthiomethyl)cephalosporins are obtained.

011 s o coou o where R is hydrogen, alkyl or alkoxy of C -C fluoro,chloro, bromo, hydroxy, amino, nitro, or trifluoromethyl or thenon-toxic pharmaceutically acceptable salts thereof.

2. A compound as claimed in claim 1 where R is hydrogen, p-hydroxy,m-amino, m-trifluoromcthyl, mnitro, m-chloro, p-methoxy or p-methyl.

3. A compound as claimed in claim 2 where the sulfur is bonded toposition 2 of the pyridine ring.

4. A compound as claimed in claim 3 being the compound 7-mandelamido-3-(I-oxido-Z- pyridylthiomethyl)-3-cephem-4-carboxylic acid.

5. A compound as claimed in claim 3 being the compound7-(4-hydroxymandelamido )-3-( l -oxido-2-pyridylthiomethyl)-3-cephem-4-carboxylic acid.

1. A COMPOUND OF THE FORMULA
 2. A compound as claimed in claim 1 where R is hydrogen, p-hydroxy, m-amino, m-trifluoromethyl, m-nitro, m-chloro, p-methoxy or p-methyl.
 3. A compound as claimed in claim 2 where the sulfur is bonded to position 2 of the pyridine ring.
 4. A compound as claimed in claim 3 being the compound 7-mandelamido-3-(1-oxido-2-pyridylthiomethyl)-3-cephem-4-carboxylic acid.
 5. A compound as claimed in claim 3 being the compound 7-(4-hydroxymandelamido)-3-(1-oxido-2-pyridylthiomethyl)-3-cephem-4 -carboxylic acid. 